Positive inotropic drugs have been widely used in the treatment of congestive heart failure, and in particular it is an important method for improving myocardial systolic functions by using positive inotropic drugs during the aggravation stage of diseases.
Currently, the conventional positive inotropic drugs mainly include:
(I) cAMP-Dependent Positive Inotropic Drugs Include:
1. β-receptor agonist: such drugs include dopamine, dobutamine and noradrenaline, which are used to improve the hemodynamic parameters of heart failure patients that suffer from myocardial function impairment in acute aggravation stage. Due to the signal dysfunction in early or late congestive heart failure (down-regulation of β-receptor and signal uncoupling), the application of β receptor agonists in the treatment of this kind of congestive heart failure only show relatively poor therapeutic effects. In addition, denopamine is also a kind of newly developed β1 receptor partial agonist for oral administration.
2. Phosphodiesterase (PDE) III inhibitor: cAMP can directly regulate the contractility and diastole of normal myocardium and produce positive inotropic effect and positive lusitropic effect. These kind of drugs can increase cAMP by inhibiting PDE III and reducing cAMP degradation, and include: amrinone, milrinone, olprinone, vesnarinone and others.
3. Adenylate cyclase agonist: such drugs include forskolin, colforsin daropate hydrochloride (i.e. Adehl or NKH-477) and others.
(II) cAMP-Independent Positive Inotropic Drugs Mainly Include:
1. Na+/K+ATPase inhibitors: they can increase the influx of Ca2+ by inhibiting Na+/K+-ATPase, such as digitalis cardiac glycoside including digoxin, digitoxin and lanatoside C.
2. Calcium sensitizer: such as pimobendam, sulmazole, thiadizinone and others, take effect on the coupled excitation-contraction process of myocardium and induce a transient Ca2+ increase, and thus increase the sensitivity of muscular fibers or the responsibility to Ca2+.
Great advancements have been achieved in the investigations on positive inotropic drugs during the past several decades, but currently available drugs have shown adverse effects in different degrees, particularly in cardiac arrhythmias and others, and the therapeutic effect is not satisfactory and thus it still needs further improvement.
Tetramethylpyrazine is one of the active ingredients of ligusticum chuanxiong hort, which has significant therapeutic effects on cardiovascular and cerebrovascular diseases with little side effects. Liguzinediol is the derivate (or derivative) of tetramethylpyrazine. The Chinese patent application 200710092853.2 disclosed that 2,5-di-(choline phosphate) methyl-3,6-dimethyl pyrazine, which is obtained by using liguzinediol as a precursor, can inhibit the activity of C-reactive protein (CRP). However, the positive inotropic activity of tetramethylpyrazine derivate has not been reported until now.